CCI-779 is rapamycin 42-ester with 3-hydroxy-2-(hydroxymethyl)-2-methylpropionic acid, an ester of rapamycin which has demonstrated significant inhibitory effects on tumor growth in both in vitro and in vivo models. This compound is now known generically under the name temsirolimus. The use of CCI-779 alone [see, e.g., U.S. Pat. No. 7,189,735] or in combination with other active agents [see, e.g., US Published Patent Application No. 2004-0258662 A1] has been described.
Renal cell carcinoma (RCC) is the most common primary renal malignant neoplasm in adults, accounting for more than 85% of all malignant kidney tumors and 2% of all adult malignancies. The majority of renal tumor malignancies arises from the tubular epithelium and is divided into several distinct subtypes based on morphologic features defined in the WHO International Histological Classification of Kidney Tumors.
The most common subtype, clear-cell renal cell carcinoma (cRCC) accounts for approximately 70-75% of all RCCs. Papillary renal cell carcinoma (pRCC) is the second most common subtype with ˜15% of cases, followed by chromophobe (˜5%), oncocytoma (˜3%), and collecting duct (˜2%).
PRCC is histologically characterized by the presence fibrovascular cores with tumor cells arranged in a papillary configuration. The majority of PRCC tumors show indolent behavior and have a limited risk of progression and mortality, but a distinct subset displays highly aggressive behavior [X. J. Yang et al, Cancer Res. 65, 5628 (2005)]. Treatment of PRCC has remained problematic. To date, no effective therapy is available for patients with advanced pRCC and patients with pRCC are usually excluded from clinical trials that are usually designed for the more common clear cell renal cell carcinoma.
Multi-kinase inhibitors, Sorafenib (Nexavar™) and Sunitinib (Sutent™), have gained FDA approval for treatment of patients with advanced renal cell carcinoma and metastatic kidney cancer. Both inhibitors are small molecule multi-receptor kinase inhibitors of VEGF, PDGFR, and others and have demonstrated improved progression-free survival with a decreased toxicity profiles compared to some of the conventional cytokine therapies. However, these clinical trials enrolled only patients with clear-cell pathology and excluded patients having non-clear cell pathology.
What are needed are effective methods for treating non-clear cell renal cell cancers.